Abstract

Human health in the current medical era is facing numerous challenges, especially cancer. So, the therapeutic arsenal for cancer should be unremittingly enriched with novel small molecules that selectively target tumour cells with minimal toxicity towards normal cells. In this context, herein a new series of 3,6-disubstituted pyridazines 11a–r has been synthesised and evaluated for in vitro anticancer activity. They possessed good anti-proliferative action towards human breast cancer T-47D (IC₅₀ range: 0.43 ± 0.01 − 35.9 ± 1.18 µM) and MDA-MB-231 (IC₅₀ range: 0.99 ± 0.03 − 34.59 ± 1.13 µM) cell lines, whereas they displayed weak activity against the tested ovarian cancer cell line SKOV-3. Among the studied compounds, the methyltetrahydropyran-bearing pyridazine 11m emerged as the unique submicromolar growth inhibitor herein reported towards both T-47D (IC₅₀ = 0.43 ± 0.01 µM) and MDA-MB-231 (IC₅₀ = 0.99 ± 0.03 µM) cell lines. In addition, the biological results indicated that pyridazines 11l and 11m exerted an efficient alteration within the cell cycle progression as well as induction of apoptosis in both T-47D and MDA-MB-231 cells. Moreover, pyridazines 11l and 11m displayed good mean tumour S. I. values of 13.7 and 16.1 upon assessment of their cytotoxicity towards non-tumorigenic breast MCF-10A cells. Furthermore, an in silico study proposed CDK2 as a probable enzymatic target for pyridazines 11, and explored their binding interactions within the vicinity of CDK2 binding site. Subsequently, pyridazines 11e, 11h, 11l, and 11m were selected to be evaluated for their ability to inhibit CDK2, where they exerted good inhibitory activity (IC₅₀ = 151, 43.8, 55.6 and 20.1 nM, respectively). Finally, the in silico study implied that target pyridazines 11 exhibited not only an efficient anticancer activity but also an acceptable ADME, physicochemical and druglikeness properties, specifically pyridazines 11l and 11m. Overall the obtained results from this study quite sustained our strategy and gave us a robust opportunity for further development and optimisation of 3,6-disubstituted pyridazine scaffold to enrich therapeutic arsenal with efficient and safe anticancer CDK inhibitors.

摘要

当前医学时代的人类健康面临众多挑战，尤其是癌症。因此，用于治疗癌症的武器库应不间断地富含新型小分子，这些小分子选择性地靶向肿瘤细胞，而对正常细胞的毒性最小。在此背景下，本文合成了一系列新的3,6-二取代哒嗪11a-r，并对其体外抗癌活性进行了评估。它们对人乳腺癌T-47D（IC ₅₀范围：0.43±0.01-35.9±1.18 µM）和MDA-MB-231（IC ₅₀）具有良好的抗增殖作用范围：0.99±0.03 − 34.59±1.13 µM），而它们对受试卵巢癌细胞SKOV-3的活性较弱。在研究的化合物中，带有甲基四氢吡喃的哒嗪11m成为本文报道的针对T-47D（IC ₅₀ = 0.43±0.01 µM）和MDA-MB-231（IC ₅₀ = 0.99±0.03 µM）细胞的独特的亚微摩尔生长抑制剂。线。另外，生物学结果表明，哒嗪11l和11m在T-47D和MDA-MB-231细胞中都在细胞周期进程中发挥了有效的改变，并诱导了细胞凋亡。此外，哒嗪11l和11m在评估它们对非致瘤性乳腺癌MCF-10A细胞的细胞毒性后，显示出良好的平均肿瘤SI值，分别为13.7和16.1。此外，计算机研究提出CDK2作为哒嗪11的可能的酶促靶标，并探讨了CDK2在CDK2结合位点附近的结合相互作用。随后，选择哒嗪11e，11h，11l和11m评估其抑制CDK2的能力，并在其中发挥良好的抑制活性（分别为IC ₅₀ = 151、43.8、55.6和20.1 nM）。最后，计算机研究表明靶标哒嗪11不仅表现出有效的抗癌活性，而且表现出可接受的ADME，理化性质和药物相似性，特别是哒嗪11l和11m。总体而言，从这项研究中获得的结果在很大程度上维持了我们的策略，并为我们进一步开发和优化3,6-二取代哒嗪支架提供了强大的机会，以用有效和安全的抗癌CDK抑制剂丰富治疗药库。